CN105622459B - A kind of method for preparing calystegine and its intermediate - Google Patents
A kind of method for preparing calystegine and its intermediate Download PDFInfo
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- CN105622459B CN105622459B CN201610015028.1A CN201610015028A CN105622459B CN 105622459 B CN105622459 B CN 105622459B CN 201610015028 A CN201610015028 A CN 201610015028A CN 105622459 B CN105622459 B CN 105622459B
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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Abstract
The present invention relates to the synthesis field of natural products, a kind of method for preparing calystegine and its intermediate is disclosed, the calystegine has the structure shown in Formulas I, and this method comprises the following steps：In the presence of protective agent, the hydroxyl in the primary alconol shown in Formula II is subjected to protection reaction；Alkene shown in formula III and ozone are reacted；Aldehyde shown in formula IV is subjected to Ylide reaction；Alkenyl iodine shown in Formula V is subjected to deprotection reaction；Alcohol shown in Formula IV is reacted with the first oxidant；Aldehyde shown in Formula VII is subjected to NHK reactions；Alcohol shown in Formula VIII is reacted with the second oxidant；Beta-unsaturated ketone shown in Formula IX is subjected to reduction reaction.The present invention is by being easy to get and cheap raw material with succinct route has efficiently synthesized calystegine.This provides new route for the synthesis of calystegine series compounds, and solid foundation is provided to screen the compound for having bioactivity and medical value.
Description
Technical field
The present invention relates to the synthesis field of natural products, in particular it relates to a kind of calystegine and its intermediate of preparing
Method.
Background technology
Calystegine (calystegine) is the alkaloid that a class has azabicyclo [3.2.1] octane structure, and it is earliest
It is from convolvulaceous plant ivy glorybind Calystegine sepium [Tepfer, D. in 1988；Goldmann,A.；
Pamboukdjian,N.；Maille,M.；Lepingle,A.；Chevalier,D.；Dénarié,J.；Rosenberg,
C.J.Bacteriol.1988,170 (3), 1153-1161] in separate, what is found so far is natural
Calystegine alkaloids have had kind more than ten, they be widely present in water fruits and vegetables (such as potato, eggplant, sweet potato) and
Insect such as moth, butterfly are (in (its larva is often using plant of Solanaceae as food).
Calystegine alkaloids have good glucoside inhibiting activity, in treating cancer, bacterium infection, diabetes
And have good application prospect in terms of glycosphingolipid storage disease.
Due to the unique structure and excellent bioactivity of calystegine alkaloids, worldwide is attracted
Interior numerous seminar carries out fully synthetic research.In addition, those skilled in the art have also synthesized a variety of similar of calystegine
Thing, and have studied the relation between their activity and its configuration.
As can be seen that calystegine is one of focus of research all the time, and therefore, a kind of efficient conjunction of development
Method into calystegine is for finding that the lead compound of new high activity has very important significance.
The content of the invention
It is easy to get it is an object of the invention to provide a kind of raw material, route is succinct and the efficient method for preparing calystegine.
To achieve these goals, in a first aspect, the method that the present invention provides the alcohol shown in a kind of formula VIII, the party
Method includes：Aldehyde shown in Formula VII is subjected to NHK reactions,
Wherein, in Formula VII and Formula VIII 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5
The spatial configuration of position carbon is each independently R configurations or S configurations；And
In Formula VII and Formula VIII, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently the straight of C1-C12
On chain or side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring by C1-C4 alkoxy or
At least one of benzyl of halogen substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl.
Second aspect, the present invention provides a kind of method for preparing calystegine, and the calystegine has the knot shown in Formulas I
Structure, this method comprises the following steps：
1) aldehyde shown in Formula VII is subjected to NHK reactions, obtains the alcohol shown in Formula VIII；
2) alcohol shown in the Formula VIII is reacted with the second oxidant, obtains the beta-unsaturated ketone shown in Formula IX；
3) beta-unsaturated ketone shown in the Formula IX is subjected to reduction reaction, obtains the calystegine shown in Formulas I；
Wherein, Formula VII into Formula IX 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5
The spatial configuration of carbon is each independently R configurations or S configurations；And
In Formula VII into Formula IX, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently C1-C12 straight chain
Or by C1-C4 alkoxy or halogen on side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of benzyl of element substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；
In Formulas I, R1For hydroxyl or amino, R2、R2’、R3、R4、R4’、R5And R6Hydrogen or hydroxyl are each independently selected from, and
R2And R2' and R4And R4' it is different when be hydrogen, R7Straight or branched saturated alkyl, pi-allyl selected from C1-C12, propylidene base, second
At least one of benzyl that hydrogen atom on acyl group, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen.
The third aspect, the present invention provides a kind of method for preparing calystegine, and the calystegine has the knot shown in Formulas I
Structure, this method comprises the following steps：
1) in the presence of protective agent, the hydroxyl in the primary alconol shown in Formula II is subjected to protection reaction, obtained shown in formula III
Alkene；
2) alkene shown in the formula III and ozone are reacted, obtains the aldehyde shown in formula IV；
3) aldehyde shown in the formula IV is subjected to Ylide reaction, obtains the alkenyl iodine shown in Formula V；
4) the alkenyl iodine shown in the Formula V is subjected to deprotection reaction, obtains the alcohol shown in VI；
5) alcohol shown in the Formula IV is reacted with the first oxidant, obtains the aldehyde shown in Formula VII；
6) aldehyde shown in the Formula VII is subjected to NHK reactions, obtains the alcohol shown in Formula VIII；
7) alcohol shown in the Formula VIII is reacted with the second oxidant, obtains the beta-unsaturated ketone shown in Formula IX；
8) beta-unsaturated ketone shown in the Formula IX is subjected to reduction reaction, obtains the calystegine shown in Formulas I；
Wherein, Formula II into Formula IX 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5
The spatial configuration of carbon is each independently R configurations or S configurations；And
In Formula II into Formula IX, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently C1-C12 straight chain
Or by C1-C4 alkoxy or halogen on side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of benzyl of element substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；R6For trimethyl silicon substrate, triethyl group silicon substrate, the tert-butyl group
Dimethyl silicon substrate, the tert-butyl group, to methoxy-benzyl, methoxyl methyl, 2- methoxyl groups ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran
At least one of base, acetyl group and benzoyl；
In Formulas I, R1For hydroxyl or amino, R2、R2’、R3、R4、R4’、R5And R6Hydrogen or hydroxyl are each independently selected from, and
R2And R2' and R4And R4' it is different when be hydrogen, R7Straight or branched saturated alkyl, pi-allyl selected from C1-C12, propylidene base, second
At least one of benzyl that hydrogen atom on acyl group, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen.
The above-mentioned preparation method raw material that the present invention is provided is easy to get, route succinct and efficient, using the preparation method of the present invention
The purity of the calystegine prepared is high.
In addition, preparing the method for calystegine relative to prior art, method of the invention also has the advantages that high income.
Other features and advantages of the present invention will be described in detail in subsequent embodiment part.
Embodiment
The embodiment to the present invention is described in detail below.It should be appreciated that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to limit the invention.
In a first aspect, the invention provides a kind of method of the alcohol shown in formula VIII, this method includes：By Formula VII
Shown aldehyde carries out NHK reactions,
Wherein, in Formula VII and Formula VIII 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5
The spatial configuration of position carbon is each independently R configurations or S configurations；And
In Formula VII and Formula VIII, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently the straight of C1-C12
On chain or side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring by C1-C4 alkoxy or
At least one of benzyl of halogen substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl.
Alcohol shown in the Formula VIII is the intermediate of the calystegine.
Preferably, NHK reaction is carried out in the presence of the first catalyst, first catalyst be selected from chromium dichloride,
At least one of Nickel Chloride, cobaltous dichloride.
Preferably, the aldehyde shown in the Formula VII and the first catalyst amount mol ratio are 1：1-100；More preferably
1：1-25.
Preferably, the condition of the NHK reactions includes：Temperature is 0-100 DEG C, and the time is 0.5-100 hours；It is further preferred that
The condition of the NHK reactions includes：Temperature is 10-65 DEG C, and the time is 5-72 hours.
Preferably, the aldehyde shown in the Formula VII is made by following steps：
1) in the presence of protective agent, the hydroxyl in the primary alconol shown in Formula II is subjected to protection reaction, obtained shown in formula III
Alkene；
2) alkene shown in the formula III and ozone are reacted, obtains the aldehyde shown in formula IV；
3) aldehyde shown in the formula IV is subjected to Ylide reaction, obtains the alkenyl iodine shown in Formula V；
4) the alkenyl iodine shown in the Formula V is subjected to deprotection reaction, obtains the alcohol shown in Formula IV；
5) alcohol shown in the Formula IV is reacted with the first oxidant, obtains the aldehyde shown in Formula VII；
Wherein, Formula II into Formula VII 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3 and 4 carbon
Spatial configuration be each independently R configurations or S configurations；And
In Formula II into Formula VII, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently C1-C12 straight chain
Or by C1-C4 alkoxy or halogen on side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of benzyl of element substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；R6For trimethyl silicon substrate, triethyl group silicon substrate, the tert-butyl group
Dimethyl silicon substrate, the tert-butyl group, to methoxy-benzyl, methoxyl methyl, 2- methoxyl groups ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran
At least one of base, acetyl group and benzoyl.
Preferably, in step 2) in, the condition that the alkene shown in formula III and ozone are reacted is included：Temperature is subzero
100 DEG C to 50 DEG C, the time is 1-60min.
Preferably, in step 3) in, the condition of the Ylide reaction includes：Temperature is subzero 100 DEG C to above freezing 100
DEG C, the time is 0.5-24 hours；The condition of more preferably described Ylide reaction includes：Temperature is subzero 78 DEG C to 25 DEG C above freezing,
Time is 2-3 hours.
Preferably, in step 4) in, the condition of the deprotection reaction includes：Temperature is 0-100 DEG C, and the time is 0.5-72
Hour.
Preferably, in step 5) in, the condition that the alcohol shown in Formula IV is reacted with the first oxidant is included：Temperature is
Subzero 100 DEG C to 100 DEG C above freezing, the time is 0.5-100 hours.
Preferably, in step 5) in, first oxidant is selected from potassium permanganate, potassium bichromate, chromium trioxide, titanium dioxide
Manganese, sodium periodate, dimethyl sulfoxide (DMSO), Dai Si-at least one of Martin's oxidant and bromine water.
Second aspect, the invention provides a kind of method for preparing calystegine, the calystegine has the knot shown in Formulas I
Structure, this method comprises the following steps：
1) aldehyde shown in Formula VII is subjected to NHK reactions, obtains the alcohol shown in Formula VIII；
2) alcohol shown in the Formula VIII is reacted with the second oxidant, obtains the beta-unsaturated ketone shown in Formula IX；
3) beta-unsaturated ketone shown in the Formula IX is subjected to reduction reaction, obtains the calystegine shown in Formulas I；
Wherein, Formula VII into Formula IX 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5
The spatial configuration of carbon is each independently R configurations or S configurations；And
In Formula VII into Formula IX, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently C1-C12 straight chain
Or by C1-C4 alkoxy or halogen on side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of benzyl of element substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；
In Formulas I, R1For hydroxyl or amino, R2、R2’、R3、R4、R4’、R5And R6Hydrogen or hydroxyl are each independently selected from, and
R2And R2' and R4And R4' it is different when be hydrogen, R7Straight or branched saturated alkyl, pi-allyl selected from C1-C12, propylidene base, second
At least one of benzyl that hydrogen atom on acyl group, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen.
Correlated response condition and response parameter of relevant NHK reactions in the second aspect of the present invention etc. are with the present invention's
It is identical described in first aspect, wherein, the aldehyde shown in the Formula VII can use the method system in the first aspect of the present invention
It is standby to obtain, it can also be prepared by other methods of this area.
The third aspect, the invention provides a kind of method for preparing calystegine, the calystegine has the knot shown in Formulas I
Structure, this method comprises the following steps：
1) in the presence of protective agent, the hydroxyl in the primary alconol shown in Formula II is subjected to protection reaction, obtained shown in formula III
Alkene；
2) alkene shown in the formula III and ozone are reacted, obtains the aldehyde shown in formula IV；
3) aldehyde shown in the formula IV is subjected to Ylide reaction, obtains the alkenyl iodine shown in Formula V；
4) the alkenyl iodine shown in the Formula V is subjected to deprotection reaction, obtains the alcohol shown in VI；
5) alcohol shown in the Formula IV is reacted with the first oxidant, obtains the aldehyde shown in Formula VII；
6) aldehyde shown in the Formula VII is subjected to NHK reactions, obtains the alcohol shown in Formula VIII；
7) alcohol shown in the Formula VIII is reacted with the second oxidant, obtains the beta-unsaturated ketone shown in Formula IX；
8) beta-unsaturated ketone shown in the Formula IX is subjected to reduction reaction, obtains the calystegine shown in Formulas I；
Wherein, Formula II into Formula IX 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5
The spatial configuration of carbon is each independently R configurations or S configurations；And
In Formula II into Formula IX, R1、R2And R3It is identical or different, and R1、R2And R3It is each independently C1-C12 straight chain
Or by C1-C4 alkoxy or halogen on side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of benzyl of element substitution；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl
At least one of base, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；R6For trimethyl silicon substrate, triethyl group silicon substrate, the tert-butyl group
Dimethyl silicon substrate, the tert-butyl group, to methoxy-benzyl, methoxyl methyl, 2- methoxyl groups ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran
At least one of base, acetyl group and benzoyl；
In Formulas I, R1For hydroxyl or amino, R2、R2’、R3、R4、R4’、R5And R6Hydrogen or hydroxyl are each independently selected from, and
R2And R2' and R4And R4' it is different when be hydrogen, R7Straight or branched saturated alkyl, pi-allyl selected from C1-C12, propylidene base, second
At least one of benzyl that hydrogen atom on acyl group, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen.
The protection of the present invention, which is reacted, to be referred to, the reaction protected using protective agent to the hydroxyl in Formula II.
The Formula II of the present invention into Formula IX 1,2,3, the spatial configuration of 4 and 5 carbon correspond to respectively it is identical refer to, Formula II is extremely
The spatial configuration of 1 carbon in Formula IX is identical, can be R configurations or S configurations；The spatial configuration of 2 carbon of the Formula II into Formula IX
It is identical, can be R configurations or S configurations, and so on.
Straight chain saturated alkyl and C3-C12 of the C1-C12 of the present invention straight or branched saturated alkyl including C1-C12
Side chain saturated alkyl.The C1-C12 refers to that carbon number is 1-12, and the C3-C12 refers to that carbon number is 3-12.It is described
C1-C12 straight chain saturated alkyl can include methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, just pungent
Base, n-nonyl, positive decyl, n-undecane base and dodecyl.The side chain saturated alkyl of the C3-C12 can include isopropyl
Base, sec-butyl, isobutyl group, the tert-butyl group, isopentyl, tertiary pentyl, neopentyl, isohesyl, different heptyl and iso-octyl.
The C1-C4 of present invention alkoxy can include methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen
Base, isobutoxy and tert-butoxy.
In the present invention, it is preferable that in Formula II into Formula IX, R1、R2And R3It is identical or different, and R1、R2And R3It is each independent
Ground is by C1- on C1-C8 straight or branched saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of C3 benzyl of alkoxy or halogen substitution；R4And R5For C1-C8 straight or branched saturated alkyl, allyl
At least one of base, acetyl group, benzyl, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；R6For trimethyl silicon substrate, triethyl group
Silicon substrate, t-Butyldimethylsilyl, the tert-butyl group, to methoxy-benzyl, methoxyl methyl, 2- methoxyl groups ethoxymethyl, oxinane
At least one of base, tetrahydrofuran base, acetyl group and benzoyl.
In the present invention, it is highly preferred that in Formula II into Formula IX, R1、R2And R3It is identical or different, and R1、R2And R3Each solely
It is on the spot quilt on C1-C4 straight or branched saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of methoxyl group or the benzyl of halogen substitution；R4And R5For C1-C4 straight or branched saturated alkyl, pi-allyl, second
At least one of acyl group, benzyl, benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethoxycarbonyl；R6For trimethyl silicon substrate, triethyl group silicon substrate,
T-Butyldimethylsilyl, the tert-butyl group, to methoxy-benzyl, methoxyl methyl, 2- methoxyl groups ethoxymethyl, THP trtrahydropyranyl, four
At least one of hydrogen furyl, acetyl group and benzoyl.
In the present invention, particularly preferably, the calystegine is the structure shown in Formulas I -1 or the structure shown in Formulas I -2：
In the third aspect of the present invention, it is preferable that the step 6) carried out in the presence of the first catalyst, described first
Catalyst is selected from least one of chromium dichloride, Nickel Chloride, cobaltous dichloride.
In the third aspect of the present invention, it is preferable that aldehyde and first catalyst amount mole shown in the Formula VII
Than for 1：1-100；More preferably 1：1-25.
In the third aspect of the present invention, it is preferable that in the step 6) in, the condition of the NHK reactions includes：Temperature
For 0-100 DEG C, the time is 0.5-100 hours；It is highly preferred that the condition of the NHK reactions includes：Temperature is 10-65 DEG C, time
For 5-72 hours.
In the third aspect of the present invention, it is preferable that in step 1) in, the primary alconol shown in Formula II rubs with protectant consumption
You are than being 1：1-10.
In the third aspect of the present invention, it is preferable that the step 1) carry out in the basic conditions.
In the third aspect of the present invention, it is preferable that in step 1) in, the condition of the protection reaction includes：Temperature is
Subzero 20 DEG C to 50 DEG C；Time is 0.5-24 hours, more preferably 5-12 hours.
In the third aspect of the present invention, in step 1) in, the protective agent includes but is not limited to chlorobenzoyl chloride, benzyloxy
Acyl chlorides, MOMCl, Boc acid anhydrides, TBSCl, TESCl.
In the third aspect of the present invention, it is preferable that in step 2) in, the alkene shown in formula III and ozone are reacted
Condition include：Temperature is subzero 100 DEG C to 50 DEG C, and the time is 1-60min.
In the third aspect of the present invention, it is preferable that in step 3) in, the Ylide reaction is deposited in witting reagents
Carried out lower, and the consumption mol ratio of the aldehyde shown in the formula IV and the witting reagents is 1：1-10.
In the third aspect of the present invention, it is preferable that in step 3) in, the condition of the Ylide reaction includes：Temperature
For subzero 100 DEG C to 100 DEG C above freezing, the time is 0.5-24 hours；It is highly preferred that the condition of the Ylide reaction includes：Temperature
Spend for subzero 78 DEG C to 25 DEG C above freezing, the time is 2-3 hours.
In the third aspect of the present invention, it is preferable that the step 4) there is progress, and the alkene shown in the Formula V in acid
Base iodine is 1 with the sour amount ratio：1-200.
In the third aspect of the present invention, it is preferable that in step 4) in, the condition of the deprotection reaction includes：Temperature
For 0-100 DEG C, the time is 0.5-72 hours.
In the third aspect of the present invention, it is preferable that in step 5) in, the alcohol shown in Formula IV and the first oxidant are carried out
The condition of reaction includes：Temperature is subzero 100 DEG C to 100 DEG C above freezing, and the time is 0.5-100 hours.
In the third aspect of the present invention, it is preferable that in step 7) in, the use of alcohol and the second oxidant shown in Formula VIII
It is 1 to measure mol ratio：1-10；It is highly preferred that the condition that the alcohol shown in the Formula VIII is reacted with the second oxidant is included：
Temperature is 0-100 DEG C, and the time is 0.5-24 hours.
In the third aspect of the present invention, it is preferable that in step 5) and step 7) in, first oxidant and described
Dioxy agent is identical or different, is each independently selected from potassium permanganate, potassium bichromate, chromium trioxide, manganese dioxide, periodic acid
At least one of sodium, dimethyl sulfoxide (DMSO), Dai Si-Martin's oxidant (Dess-Martin reagents) and bromine water.
In the third aspect of the present invention, it is preferable that the step 8) carry out in the presence of a catalyst, the catalyst bag
Include but be not limited to Pd/C, Pd (OH)2, palladium black, platinum catalyst etc., or lewis acid such as boron chloride, Boron tribromide etc., preferably
The catalyst system and catalyzing constituted for Pd/C and hydrochloric acid.
Pentose of the present invention partly to protect is prepared for natural products calystegine as raw material by the reaction of several steps
And the like, realize succinct, the efficient preparation of such compound.The present invention is raw materials used cheap and is easy to get, and is
The synthesis of calystegine series compounds provides new route, has bioactivity and medical value for screening
Compound provides solid foundation.
Moreover, the present invention is using the pentose partly protected as raw material, with the NHK of intramolecular (Nozaki-Hiyama-
Kishi it is) one of committed step, completes the synthesis of calystegine series compounds.It is succinct, high so as to invent one
The method for preparing the series compound of effect.
The present invention will be described in detail by way of examples below.
Below in case of no particular description, used various raw materials are all from commercially available.
Embodiment 1
Embodiment 1 is used for the calystegine shown in synthesis type I-1.
The present embodiment is carried out using following steps：
1) synthesis of the compound of Formula II -1：
In the dichloromethane that 2,3,4- tribenzyl-D- xyloses (26mmol) are dissolved in 50mL dryings, benzyl is added into solution
Amine (0.26mol), p-methyl benzenesulfonic acid (26mmol) and the molecular sieve activated, (25 DEG C) of normal temperature are stirred 3 days, and TLC monitorings are former
Material reaction is complete.Reaction is filtered to remove insoluble matter after terminating, and water is added into solution, with dichloromethane (3 × 20mL extractions), closes
And extract, filtering after anhydrous magnesium sulfate is dried, it is concentrated in vacuo and removes solvent, obtained oily liquids ethyl alcohol recrystallization is obtained
To N, O- acetals are compound as white solid, yield 87%.
By the N of gained, O- acetals (9.4mmol) are dissolved in the THF of 30mL dryings, 0 DEG C of 1.6M by vinylimidazolium chloride magnesium
THF solution (23.5mL) be slowly added in reaction solution, be slowly increased to after completion of dropwise addition room temperature and at this temperature reaction it is 48 small
When.Reaction adds saturated aqueous ammonium chloride after terminating and reaction is quenched, and is extracted with ethyl acrylate (EA) (3 × 20mL), merges
Extract, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtained crude product chromatography post separation (acetic acid second
Ester：Petroleum ether=1:8) secondary amine is obtained, is pale yellowish oil liquid, yield 89%, purity 96%.
The secondary amine structural identification is：1H NMR(300MHz,CDCl3)δ7.30–7.23(m,20H),5.79–5.68(m,
1H), 5.20 (dd, J=10.2,1.4Hz, 1H), 5.01 (d, J=17.2Hz, 1H), 4.80-4.74 (m, 2H), 4.69 (d, J=
11.4Hz, 1H), 4.59 (d, J=6.4Hz, 1H), 4.55 (d, J=6.8Hz, 1H), 4.35 (d, J=11.7Hz, 1H), 4.02
(dd, J=6.3,4.6Hz, 1H), 3.81 (d, J=13.1Hz, 1H), 3.78-3.73 (m, 2H), 3.65 (dd, J=11.8,
4.2Hz, 1H), 348-3.42 (m, 2H), 3.09 (dd, J=8.3,4.1Hz, 1H)；13C NMR(75MHz,CDCl3)δ140.33,
138.56,138.43,138.21,137.94,128.69,128.45,128.41,128.35,128.14,127.85,127.79,
127.66,127.00,117.66,82.47,80.02,78.51,74.83,74.49,72.20,61.70,60.65,50.46。
Above-mentioned secondary amine (1mmol) is dissolved in 10mL tetrahydrofurans, one is added into solution and drips water, then by NaHCO3
(2mmol), benzyl chloroformate (CbzCl) (1.2mmol) are separately added into solution, and normal-temperature reaction is stayed overnight.Reaction terminates backward molten
Water is added in liquid, is extracted with EA (3 × 10mL), combining extraction liquid, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo removing molten
Agent, obtained crude product chromatography post separation (ethyl acetate：Petroleum ether=1:10) primary alconol shown in Formula II -1 is obtained, is colourless
Oily liquids, yield 93%, purity 98%.
Primary alconol structural identification shown in the Formula II -1 is：1H NMR(400MHz,CDCl3)δ7.38–7.33(m,25H),
6.11(br,1H),5.28-525(m,2H),5.09–5.00(m,2H),4.72–4.35(m,10H),3.84–3.61(m,4H),
2.24(br,1H)；13C NMR(100MHz,CDCl3)δ156.32,138.52,138.37,138.33,136.49,134.59,
128.46,128.35,128.23,128.12,128.05,127.79,127.64,127.06,119.26,79.22,79.15,
78.94,74.57,74.24,72.94,67.30,62.12,61.66,51.79。
2) synthesis of the compound of formula III -1：
The compound of Formula II -1 (0.5mmol) is dissolved in 10mL dichloromethane, then by DIPEA (1mmol), MOMCl
(0.75mmol) is separately added into solution, and normal-temperature reaction is stayed overnight.Reaction terminates to add water in backward solution, with dichloromethane (3 ×
10mL) extract, combining extraction liquid, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtained crude product chromatography
Post separation (ethyl acetate：Petroleum ether=1：10) alkene shown in formula III -1 is obtained, is no oily liquids, yield 90%, purity
96%.
Alkene structural identification shown in formula III -1 is：1H NMR(300MHz,CDCl3)δ7.27–7.19(m,25H),5.98
(br,1H),5.15(br,2H),4.98–4.88(m,2H),4.65–4.24(m,12H),3.87(br,1H),3.65–3.51(m,
3H),3.31(s,3H)；13C NMR(75MHz,CDCl3)δ156.06,138.55,138.46,138.34,136.43,134.65,
128.32,128.19,128.10,128.03,127.91,127.75,127.46,127.40,127.30,126.85,118.84,
96.52,79.15,78.83,78.48,77.17,74.41,74.24,72.96,67.30(2C),62.03,55.14,51.70。
3) synthesis of the compound of formula IV -1：
The compound of formula III -1 (1.5mmol) is dissolved in 100mL dichloromethane, -78 DEG C are passed through ozone into solution and hold
Continuous 5min, then to argon gas is passed through in solution, adds dimethyl sulphide and is warmed to room temperature solution, 8h is stirred at room temperature.Reaction
Reaction solution is concentrated in vacuo after end, the crude product of the aldehyde shown in formula IV -1 is obtained.
4) synthesis of the compound of Formula V -1：
In the tetrahydrofuran solution that microcosmic salt (3mmol) is dissolved in 10mL dryings, 1M is added thereto under argon gas protective condition
Two (trimethyl silicon substrate) Sodamide (NaHDMS) tetrahydrofuran solutions (3mL), stirring at normal temperature 30min after completion of dropwise addition, now
Solution becomes reddish black, shows that witting reagents are successfully prepared.Reaction solution is down to -78 DEG C, by freshly prepd above-mentioned formula IV -1
The crude product of shown aldehyde is dissolved in the tetrahydrofuran of 5mL dryings and is added dropwise, and solution is warmed to room temperature and in room after 30min
Temperature is lower to be continued to stir 30min.Reaction terminates to add water in backward solution, is extracted with EA (3 × 10mL), combining extraction liquid is anhydrous
Magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtained crude product chromatography post separation (ethyl acetate：Petroleum ether=
1：10), obtain the alkenyl iodine shown in Formula V -1, be colourless oil liquid, step 3) and step 4) two step gross production rates be 80%, it is pure
Degree 97%.
Alkenyl iodine structural identification shown in Formula V -1 is：1H NMR(400MHz,CDCl3)δ7.41–7.28(m,25H),6.70
(br,1H),6.48(s,1H),5.29(s,2H),5.13(s,1H),4.88–4.44(m,11H),4.22–3.77(m,4H),
3.43(s,3H)；13C NMR(100MHz,CDCl3)δ156.41,138.81,138.61,138.52,138.27,137.76,
136.29,128.37,128.22,128.19,128.17,128.00,127.96,127.91,127.50,127.42,126.81,
96.58,86.09,79.29,78.80,78.01,74.72,74.67,73.27,67.30(2C),62.58,55.26,51.04。
5) synthesis of the compound of Formula IV -1：
The compound of Formula V -1 (0.5mmol) is dissolved in 1N methanol solution, stirring at normal temperature 24h, TLC monitoring raw material reaction
Completely, it is concentrated in vacuo and removes solvent, crude product uses column chromatography (ethyl acetate：Petroleum ether=1：8) obtain shown in Formula IV -1
Alcohol, be colourless oil liquid, yield 96%, purity 97%.
Alcohol structural identification shown in Formula IV -1 is：1H NMR(400MHz,CDCl3)δ7.34–7.23(m,25H),6.61
(br, 1H), 6.41 (d, J=7.2Hz, 1H), 5.18 (s, 2H), 4.94 (s, 1H), 4.78-4.32 (m, 9H), 3.70-3.62
(m,4H),2.09(br,1H)；13C NMR(100MHz,CDCl3)δ156.60,138.78,138.47,138.30,138.05,
137.74,136.37,128.55,128.49,128.47,128.45,128.37,128.30,128.15,127.83,127.03,
86.56,79.33,79.07,78.89,74.76,74.71,73.10,67.70,61.73,51.27。
6) synthesis of the compound of Formula VII -1：
Chloroacetic chloride (0.3mmol) is dissolved in the dichloromethane of 5mL dryings and -78 DEG C are cooled to, at this temperature will
DMSO (0.45mmol) dichloromethane solution is added dropwise, and stirs 20min after completion of dropwise addition at this temperature.By the institute of Formula IV -1
Dichloromethane (3mL) solution of the alcohol (0.15mmol) shown is added dropwise and continues to stir at this temperature, and three are added after 20min
Ethamine (0.75mmol) simultaneously goes to 30min is stirred at room temperature.Reaction terminates to add dichloromethane (20mL) in backward solution, with water (3
× 10mL) to wash, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtains the aldehyde shown in VII-1.
7) synthesis of the compound of Formula VIII -1：
By CrCl2(1.5mmol) and NiCl2(0.015mmol) is dissolved in the DMF of 30mL dryings, will under argon gas protective condition
The DMF solution of aldehyde shown in freshly prepd VII-1 is added dropwise, and 30h is stirred at room temperature after completion of dropwise addition.Reaction terminates backward solution
Middle addition water 100mL, is extracted, combining extraction liquid with EA (3 × 30mL), and water (3 × 30mL) washes mistake after rear anhydrous magnesium sulfate is dried
Filter, is concentrated in vacuo and removes solvent.The crude product of gained chromatographic column (ethyl acetate：Petroleum ether=1：8) separate, obtain formula
Alcohol shown in VIII-1, purity is 98%, step 6) and step 7) two-step reaction gross production rate be 78%.
8) synthesis of the compound of Formula IX -1：
By DMP (0.15mmol) and NaHCO3(0.22mmol) is dissolved in the dichloromethane of 5mL dryings, stirring at normal temperature
5min, the alcohol (0.07mmol) shown in Formula VIII -1 is added in reaction solution and continues to stir 2h in room temperature.Reaction adds after terminating
Enter saturated sodium thiosulfate solution, extracted with dichloromethane (3 × 10mL), combining extraction liquid, anhydrous magnesium sulfate is filtered after drying,
It is concentrated in vacuo and removes solvent, obtained crude product chromatography post separation (ethyl acetate：Petroleum ether=1：10) institute of Formula IX -1 is obtained
The beta-unsaturated ketone shown, is colourless oil liquid, yield 91%, purity 96%.
Beta-unsaturated ketone structural identification shown in Formula IX -1 is：1H NMR(300MHz,DMSO)δ7.29–7.23(m,25H),
6.60 (d, J=12.3Hz, 1H), 5.81 (d, J=12.2Hz, 1H), 5.13 (s, 2H), 5.09-5.06 (m, 1H), 4.81 (d, J
=15.8Hz, 1H), 4.65-4.42 (m, 6H), 4.25-4.11 (m, 4H)13C NMR(75MHz,DMSO)δ197.12,
155.07,147.68,137.73,137.32,137.19,136.64,135.97,127.75,127.63,127.58,127.48,
127.18,127.09,127.03,126.97,126.90,126.85,126.73,126.49,126.08,83.21,82.27,
80.33,72.58,71.64,71.15,66.22,58.94,52.20。
9) synthesis of the compound of Formulas I -1：
Beta-unsaturated ketone (0.07mmol) shown in Formula IX -1 is dissolved in 5mL acetic acid, 20mg palladium carbons are added under ar gas environment,
Normal-temperature reaction 3 days after hydrogen is replaced three times.Reaction is filtered to remove palladium carbon after terminating, concentration removes acetic acid, adds 1mL ammoniacal liquor then
It is spin-dried for, in triplicate, crude product cationic ion-exchange resin (Dowex, 5w × 8-400, H+Type, Aldrich) processing, obtain formula
I-1 compounds, are colourless oil liquid, yield 81%, purity 95%.
The compound structure of Formulas I -1 is confirmed：1H NMR(400MHz,D2O) δ 3.56 (dd, J=8.4,3.9Hz, 1H), 3.40
(d, J=8.5,1H), 3.33 (t, J=8.3,1H), 3.30-3.28 (m, 1H), 2.02-1.97 (m, 1H), 1.96-1.90 (m,
1H),1.78–1.71(m,1H),1.56–1.48(m,1H)；13C NMR(100MHz,D2O)δ93.02,80.27,77.52,
77.47,58.43,31.36,24.31。
Embodiment 2
Embodiment 2 is used for the calystegine shown in synthesis type I-2.
The present embodiment is carried out using following steps：
1) synthesis of the compound of Formula II -2：
By 2,3,4- tribenzyls-D-R (26mmol) are dissolved in the dichloromethane of 50mL dryings, are added into solution
Enter benzylamine (0.26mol), p-methyl benzenesulfonic acid (26mmol) and the molecular sieve activated, stirring at normal temperature 3 days, TLC monitoring raw materials
Reaction is complete.Reaction is filtered to remove insoluble matter after terminating, and water is added into solution, with dichloromethane (3 × 20mL extractions), merges
Extract, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, and obtained oily liquids ethyl alcohol recrystallization is obtained
N, O- acetal, are yellow oily liquid, yield 87%.
By gained N, O- acetals (9.0mmol) are dissolved in the THF of 30mL dryings, 0 DEG C of 1.6M's by vinylimidazolium chloride magnesium
THF solution (22.5mL) is slowly added in reaction solution, and room temperature is slowly increased to after completion of dropwise addition and 48h is reacted at this temperature.Instead
Saturated aqueous ammonium chloride is added after should terminating reaction is quenched, extracted with EA (3 × 20mL), combining extraction liquid, anhydrous magnesium sulfate
Filtered after drying, be concentrated in vacuo and remove solvent, obtained crude product chromatography post separation (ethyl acetate：Petroleum ether=1：8)
It is pale yellowish oil liquid, yield 85%, purity 97% to secondary amine.
The secondary amine structural identification is：1H NMR(400MHz,CDCl3)δ7.33–7.25(m,20H),5.84–5.75
(m, 1H), 5.26 (d, J=10.2Hz, 1H), 5.13 (d, J=17.3Hz, 1H), 4.78-4.74 (m, 2H), 4.70 (d, J=
11.2Hz,1H),4.60–4.54(m,3H),4.13(m,1H),3.84–3.77(m,3H),3.70–3.65(m,2H),3.52(d,
J=13.1Hz, 1H), 3.29 (dd, J=8.3,4.7Hz, 1H), 2.38-2.28 (m, 2H)；13C NMR(100MHz,CDCl3)δ
140.06,138.64,138.57,138.28,138.01,128.47,128.41,128.37,128.35,127.90,127.82,
127.74,127.71,127.63,127.57,127.01,118.36,82.70,79.81(2C),74.94,74.50,71.66,
61.81,61.12,50.63。
The secondary amine (2.4mmol) is dissolved in 10mL tetrahydrofurans, one is added into solution and drips water, then will
NaHCO3(4.8mmol), CbzCl (2.9mmol) are separately added into solution, and normal-temperature reaction is stayed overnight.Reaction terminates in backward solution
Water is added, is extracted with EA (3 × 10mL), combining extraction liquid, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtains
The crude product arrived chromatography post separation (ethyl acetate：Petroleum ether=1：10) primary alconol shown in Formula II -2 is obtained, is colorless oil
Liquid, yield 90%, purity 98%.
Primary alconol structural identification shown in the Formula II -2 is：1H NMR(300MHz,DMSO)δ7.35–7.20(m,25H),
6.06-5.94 (m, 1H), 5.11 (s, 2H), 5.06 (d, J=10.3Hz, 1H), 4.91 (d, J=17.4Hz, 1H), 4.74-
4.29 (m, 10H), 3.94 (d, J=11.2Hz, 1H), 3.77 (s, 2H), 3.68 (d, J=11.3Hz, 1H)；13C NMR
(75MHz,DMSO)δ155.33,138.49,138.34,138.29,138.14,136.21,134.72,127.59,127.45,
127.39,127.31,127.20,127.07,126.78,126.68,126.53,126.12,118.00,79.84,78.56,
78.07,73.12,72.45,70.53,66.00,61.54,59.69,50.54。
2) synthesis of the compound of formula III -2：
The compound of Formula II -2 (5.9mmol) is dissolved in 10mL dichloromethane, then by DIPEA (11.8mmol), MOMCl
(8.9mmol) is separately added into solution, and normal-temperature reaction is stayed overnight.Reaction terminates to add water in backward solution, with dichloromethane (3 ×
10mL) extract, combining extraction liquid, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtained crude product chromatography
Post separation (ethyl acetate：Petroleum ether=1：10) alkene shown in formula III -2 is obtained, is no oily liquids, yield 92%, purity
99%.
Alkene structural identification shown in formula III -2 is：1H NMR(300MHz,DMSO)δ7.34–7.20(m,25H),6.06–
5.95 (m, 1H), 5.12 (s, 2H), 5.07 (d, J=10.3Hz, 1H), 4.92 (d, J=17.3Hz, 1H), 4.75-4.47 (m,
10H), 4.39 (d, J=15.7Hz, 1H), 4.29-4.26 (m, 1H), 3.96-3.92 (m, 2H), 3.76-3.70 (m, 2H),
3.27(s,3H)；13C NMR(75MHz,DMSO)δ155.34,138.23,138.15,136.17,134.57,127.60,
127.49,127.41,127.31,127.22,127.10,126.76,126.66,126.64,126.30,126.14,118.06,
95.97,78.76,78.45,73.27,72.54,70.76,66.54,66.05,61.49,54.28,50.49。
3) synthesis of the compound of formula IV -2：
III-2 (1.0mmol) is dissolved in 70mL dichloromethane, -78 DEG C are passed through ozone into solution and continue 5min, with
Argon gas is passed through in backward solution, dimethyl sulphide is added and is warmed to room temperature solution, 8h is stirred at room temperature.Reaction will be anti-after terminating
Answer liquid to be concentrated in vacuo, obtain the crude product of the aldehyde shown in formula IV -2.
4) synthesis of the compound of Formula V -2：
In the tetrahydrofuran solution that microcosmic salt (2mmol) is dissolved in 10mL dryings, 1M is added thereto under argon gas protective condition
NaHDMS tetrahydrofuran solutions (3mL), stirring at normal temperature 30min after completion of dropwise addition, now solution become reddish black, show
Witting reagents are successfully prepared.Reaction solution is down to -78 DEG C, the crude product of the aldehyde shown in freshly prepd above-mentioned formula IV -2 is molten
In the tetrahydrofuran that 5mL is dried and it is added dropwise, solution is warmed to room temperature after 30min and continues stirring 30min at room temperature.
Reaction terminates to add water in backward solution, is extracted with EA (3 × 10mL), combining extraction liquid, and anhydrous magnesium sulfate is filtered after drying, very
Sky concentration removes solvent, obtained crude product chromatography post separation (ethyl acetate：Petroleum ether=1：10), obtain shown in Formula V -2
Alkenyl iodine, be colourless oil liquid, step 3) and step 4) two step gross production rates be 75%, purity 96%.
Alkenyl iodine structural identification shown in Formula V -2 is：1H NMR(300MHz,DMSO)δ7.34–7.20(m,25H),
6.06-5.95 (m, 1H), 5.12 (s, 2H), 5.07 (d, J=10.3Hz, 1H), 4.92 (d, J=17.3Hz, 1H), 4.75-
4.47 (m, 10H), 4.39 (d, J=15.7Hz, 1H), 4.29-4.26 (m, 1H), 3.96-3.92 (m, 2H), 3.76-3.70 (m,
2H),3.27(s,3H)；13C NMR(75MHz,DMSO)δ155.34,138.23,138.15,136.17,134.57,127.60,
127.49,127.41,127.31,127.22,127.10,126.76,126.66,126.64,126.30,126.14,118.06,
95.97,78.76,78.45,73.27,72.54,70.76,66.54,66.05,61.49,54.28,50.49。
5) synthesis of the compound of Formula IV -2：
The compound of Formula V -2 (0.7mmol) is dissolved in 1N methanol solution, stirring at normal temperature 24h, TLC monitoring raw material reaction
Completely, it is concentrated in vacuo and removes solvent, crude product uses column chromatography (ethyl acetate：Petroleum ether=1：8) obtain shown in Formula IV -2
Alcohol, be colourless oil liquid, yield 96%, purity 98%.
Alcohol structural identification shown in Formula IV -2 is：1H NMR(300MHz,DMSO)δ7.35–7.16(m,25H),6.67–
6.58 (m, 2H), 5.08-5.01 (m, 3H), 4.74-4.52 (m, 7H), 4.42 (d, J=11.4Hz, 1H), 4.25-4.23 (m,
1H), 3.91 (d, J=11.0Hz, 1H), 3.75-3.66 (m, 3H)；13C NMR(75MHz,DMSO)δ155.37,138.45,
138.31,138.10,137.41,136.04,127.52,127.42,127.36,127.26,127.01,126.84,126.75,
126.63,126.52,125.95,87.60,80.02,78.02,73.22,72.53,70.66,66.15,62.10,59.80,
49.43。
6) synthesis of the compound of Formula VII -2：
Chloroacetic chloride (0.8mmol) is dissolved in the dichloromethane of 5mL dryings and -78 DEG C are cooled to, at this temperature will
DMSO (1.2mmol) dichloromethane solution is added dropwise, and stirs 20min after completion of dropwise addition at this temperature.By the institute of Formula IV -2
Dichloromethane (3mL) solution of the alcohol (0.4mmol) shown is added dropwise and continues to stir at this temperature, and three are added after 20min
Ethamine (2mmol) simultaneously goes to 30min is stirred at room temperature.Reaction terminates to add dichloromethane (20mL) in backward solution, with water (3 ×
10mL) wash, anhydrous magnesium sulfate is filtered after drying, and is concentrated in vacuo and is removed solvent, obtains the aldehyde shown in VII-2.
7) synthesis of the compound of Formula VIII -2：
By CrCl2(4mmol) and NiCl2(0.02mmol) is dissolved in the DMF of 30mL dryings, will be new under argon gas protective condition
The DMF solution of aldehyde shown in the VII-2 of preparation is added dropwise, and 30h is stirred at room temperature after completion of dropwise addition.Reaction terminates in backward solution
Water 100mL is added, is extracted with EA (3 × 30mL), combining extraction liquid, water (3 × 30mL) is washed after rear anhydrous magnesium sulfate is dried and filtered,
It is concentrated in vacuo and removes solvent.The crude product of gained chromatographic column (ethyl acetate：Petroleum ether=1：8) separate, obtain Formula VIII -2
Shown alcohol, is colourless oil liquid, step 6) and step 7) two-step reaction gross production rate be 70%, purity 97%.
Alcohol structural identification shown in Formula VIII -2 is：1H NMR(300MHz,DMSO)δ7.34–7.23(m,25H),5.67–
5.58(m,1H),5.54–5.40(m,1H),5.15–5.07(m,2H),4.82–4.53(m,7H),4.31–4.26(m,3H),
4.13–4.01(m,2H),3.90–3.87(m,1H)；13C NMR(75MHz,DMSO)δ155.18,138.53,138.33,
137.95,136.21,130.69,127.55,127.44,126.91,126.82,126.75,126.60,126.53,126.26,
126.11,81.17,80.20,78.87,71.94,71.79,71.66,68.09,65.90,59.94,50.38。
8) synthesis of the compound of Formula IX -2：
By DMP (0.63mmol) and NaHCO3(0.42mmol) is dissolved in the dichloromethane of 5mL dryings, stirring at normal temperature
5min, the alcohol (0.21mmol) shown in Formula VIII -2 is added in reaction solution and continues to stir 2h in room temperature.Reaction adds after terminating
Enter saturated sodium thiosulfate solution, extracted with dichloromethane (3 × 10mL), combining extraction liquid, anhydrous magnesium sulfate is filtered after drying,
It is concentrated in vacuo and removes solvent, obtained crude product chromatography post separation (ethyl acetate：Petroleum ether=1：10) institute of Formula IX -2 is obtained
The beta-unsaturated ketone shown, is colourless oil liquid, yield 93%, purity 99%.
Beta-unsaturated ketone structural identification shown in Formula IX -2 is：1H NMR(300MHz,DMSO)δ7.34–7.23(m,25H),
5.67–5.58(m,1H),5.54–5.40(m,1H),5.15–5.07(m,2H),4.82–4.53(m,7H),4.31–4.26(m,
3H),4.13–4.01(m,2H),3.90–3.87(m,1H)；13C NMR(75MHz,DMSO)δ155.18,138.53,138.33,
137.95,136.21,130.69,127.55,127.44,126.91,126.82,126.75,126.60,126.53,126.26,
126.11,81.17,80.20,78.87,71.94,71.79,71.66,68.09,65.90,59.94,50.38。
9) synthesis of the compound of Formulas I -2：
Beta-unsaturated ketone (0.1mmol) shown in Formula IX -2 is dissolved in 5mL acetic acid, 20mg palladium carbons are added under ar gas environment,
Normal-temperature reaction 3 days after hydrogen is replaced three times.Reaction is filtered to remove palladium carbon after terminating, concentration removes acetic acid, adds 1mL ammoniacal liquor then
It is spin-dried for, in triplicate, crude product anion exchange resin (Amberlite IRA-400, OH-Type, Alfa, column dimension：1.3
× 14cm) processing, the compound of Formulas I -2 is obtained, is colourless oil liquid, yield is 80%, purity 96%.
The compound structure of Formulas I -2 is confirmed：1H NMR(400MHz,D2O) δ 3.82 (d, J=3.7Hz, 1H), 3.64 (dd, J
=9.4,3.4Hz, 1H), 3.60 (dd, J=9.4,3.8Hz, 1H), 3.26 (dd, J=6.8,3.4Hz, 1H), 1.93-1.88
(m,1H),1.79–1.71(m,3H)；13C NMR(100MHz,D2O)δ92.96,77.29,75.31,73.06,58.32,
34.17,23.02。
From above-described embodiment 1 and embodiment 2 as can be seen that by the present invention in that with being easy to get and cheap raw material is with succinct
Route has efficiently synthesized calystegine.This provides a new route for the synthesis of calystegine series compounds, for sieve
Choosing has bioactivity and the compound of medical value to provide solid foundation.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should equally be considered as content disclosed in this invention.
Claims (11)
1. a kind of method of the alcohol shown in formula VIII, this method includes：Aldehyde shown in Formula VII is subjected to NHK reactions,
Wherein, in Formula VII and Formula VIII 1,2, the spatial configuration of 3 and 4 carbon correspond to respectively it is identical, and 1,2,3,4 and 5 carbon
Spatial configuration be each independently R configurations or S configurations；And
In Formula VII and Formula VIII, R1、R2And R3It is identical or different, and R1、R2And R3Be each independently C1-C12 straight chain or
By C1-C4 alkoxy or halogen on side chain saturated alkyl, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring
At least one of substituted benzyl；R4And R5For C1-C12 straight or branched saturated alkyl, pi-allyl, acetyl group, benzyl,
At least one of benzyloxycarbonyl group, tertbutyloxycarbonyl and fluorenylmethoxycarbonyl；
Wherein, this method also includes：Using the aldehyde shown in following steps formula VII：
1) in the presence of protective agent, the hydroxyl in the primary alconol shown in Formula II is subjected to protection reaction, the alkene shown in formula III is obtained；
2) alkene shown in the formula III and ozone are reacted, obtains the aldehyde shown in formula IV；
3) aldehyde shown in the formula IV is subjected to Ylide reaction, obtains the alkenyl iodine shown in Formula V；
4) the alkenyl iodine shown in the Formula V is subjected to deprotection reaction, obtains the alcohol shown in Formula IV；
5) alcohol shown in the Formula IV is reacted with the first oxidant, obtains the aldehyde shown in Formula VII；
Wherein, Formula II into Formula IV 1,2, the spatial configurations of 3 and 4 carbon respectively with 1 in Formula VII, 2,3 and 4 carbon it is vertical
Body configuration correspondence is identical；And
R of the Formula II into Formula IV1、R2、R3、R4And R5Respectively with the R in Formula VII1、R2、R3、R4And R5Correspondence is identical；R6For front three
Base silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, the tert-butyl group, to methoxy-benzyl, methoxyl methyl, 2- methoxyl group ethoxies
At least one of methyl, THP trtrahydropyranyl, tetrahydrofuran base, acetyl group and benzoyl.
2. according to the method described in claim 1, wherein, NHK reaction is carried out in the presence of the first catalyst, described first
Catalyst is selected from least one of chromium dichloride, Nickel Chloride and cobaltous dichloride.
3. method according to claim 2, wherein, aldehyde and first catalyst amount mole shown in the Formula VII
Than for 1：1-100.
4. method according to claim 3, wherein, aldehyde and first catalyst amount mole shown in the Formula VII
Than for 1：1-25.
5. the method according to any one in claim 1-3, wherein, the condition of the NHK reactions includes：Temperature is 0-
100 DEG C, the time is 0.5-100 hours.
6. method according to claim 5, wherein, the condition of the NHK reactions includes：Temperature is 10-65 DEG C, and the time is
5-72 hours.
7. according to the method described in claim 1, wherein, in step 3) in, the condition of the Ylide reaction includes：Temperature is
Subzero 100 DEG C to 100 DEG C above freezing, the time is 0.5-24 hours.
8. method according to claim 7, wherein, in step 3) in, the condition of the Ylide reaction includes：Temperature is
Subzero 78 DEG C to 25 DEG C above freezing, the time is 2-3 hours.
9. according to the method described in claim 1, wherein, in step 5) in, the alcohol shown in Formula IV and the first oxidant are carried out
The condition of reaction includes：Temperature is subzero 100 DEG C to 100 DEG C above freezing, and the time is 0.5-100 hours.
10. according to the method described in claim 1, wherein, in step 5) in, first oxidant is selected from potassium permanganate, again
At least one in potassium chromate, chromium trioxide, manganese dioxide, sodium periodate, dimethyl sulfoxide (DMSO), Dai Si-Martin's oxidant and bromine water
Kind.
11. a kind of method for preparing calystegine, the calystegine has the structure shown in Formulas I, this method comprises the following steps：
1 ') as the alcohol shown in the method formula VIII described in any one in claim 1-10；
2 ') alcohol shown in the Formula VIII is reacted with the second oxidant, obtains the beta-unsaturated ketone shown in Formula IX；
3 ') beta-unsaturated ketone shown in the Formula IX is subjected to reduction reaction, obtains the calystegine shown in Formulas I；
Wherein, in Formula IX 1,2, the spatial configurations of 3 and 4 carbon respectively with 1 in Formula VII, the spatial configuration of 2,3 and 4 carbon
Correspondence is identical；And
R in Formula IX1、R2、R3、R4And R5Respectively with the R in Formula VII1、R2、R3、R4And R5Correspondence is identical；
In Formulas I, R1For hydroxyl or amino, R2、R2’、R3、R4、R4’、R5And R6It is each independently selected from hydrogen or hydroxyl, and R2With
R2' and R4And R4' it is different when be hydrogen, R7Straight or branched saturated alkyl, pi-allyl, propylidene base, acetyl selected from C1-C12
At least one of benzyl that hydrogen atom on base, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen.
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Citations (2)
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|---|---|---|---|---|
| DE10317528A1 (en) * | 2003-04-16 | 2004-11-11 | Martin-Luther-Universität Halle-Wittenberg | Production of calystegines for use as glycosidase inhibitors in treating diseases such as cancer, viral infections and diabetes, comprises extraction from the leaves of Solanaceae plants |
| CN1750834A (en) * | 2003-02-18 | 2006-03-22 | 纽约大学西奈山医学院 | Combination therapy for treating protein deficiencies |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1750834A (en) * | 2003-02-18 | 2006-03-22 | 纽约大学西奈山医学院 | Combination therapy for treating protein deficiencies |
| DE10317528A1 (en) * | 2003-04-16 | 2004-11-11 | Martin-Luther-Universität Halle-Wittenberg | Production of calystegines for use as glycosidase inhibitors in treating diseases such as cancer, viral infections and diabetes, comprises extraction from the leaves of Solanaceae plants |
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| New Access to Unsaturated Keto Carba Sugars (Gabosines) Using an Intramolecular Nozaki-Kishi Reaction as the Key Step;Andre´ Lubineau和Isabelle Billault;《J. Org. Chem》;19980721;第63卷;5668-5671页 * |
| Short syntheses of enantiopure calystegine B2, B3, and B4;Philip R. Skaanderup和Robert Madsen;《Chem. Commun.》;20010531;1106-1107页 * |
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